David Huntsman

Evaluating Ovarian Cancer Risk–Reducing Salpingectomy Acceptance: A Survey

Abstract With evidence that salpingectomy is effective in preventing high-grade serous carcinoma, it is time to consider offering this procedure to people at higher-than-average lifetime risk for ovarian cancer, despite not having a pathogenic genetic variant that increases the risk for ovarian cancer. This targeted approach has potential to be effective at reducing ovarian cancer incidence, and unlike opportunistic salpingectomy, it is focused on people with an increased lifetime risk of ovarian cancer. However, the acceptability of this approach within the population of potential patients remains unknown. We conducted an online survey of adults in British Columbia, Canada, who were defined as “at risk” for ovarian cancer (i.e., people born with ovaries). Participants completed a questionnaire on demographics, ovarian cancer risk and protective factors, concerns about risk-reducing salpingectomy (RSS), and the risk they considered high enough to warrant RRS. We included 211 participants. Among these participants, 42% (n = 88) indicated that they would consider RRS at any lifetime risk or any risk above the population average. Another 20 participants chose risks between 1.5% and 4% for a cumulative 51% of the sample choosing risks below thresholds for oophorectomy. In contrast, 6% (n = 12) indicated that they would not consider the procedure at any risk level. None of the factors collected were associated with the likelihood that a person would find RRS acceptable. Overall, our participants showed broad interest in RRS as an ovarian cancer prevention strategy. These results suggest that there would likely be uptake if RRS was offered. Significance: This study found that many participants were willing to consider RRS to prevent ovarian cancer. Further research on RRS should be undertaken to understand how this can be best used for ovarian cancer prevention.

Targeted and Shallow Whole-Genome Sequencing Identifies Therapeutic Opportunities in p53abn Endometrial Cancers

Abstract Purpose: Shallow whole-genome sequencing (sWGS) can detect copy-number (CN) aberrations. In high-grade serous ovarian cancer (HGSOC) sWGS identified CN signatures such as homologous recombination deficiency (HRD) to direct therapy. We applied sWGS with targeted sequencing to p53abn endometrial cancers to identify additional prognostic stratification and therapeutic opportunities. Experimental Design: sWGS and targeted panel sequencing was performed on formalin-fixed, paraffin-embedded p53abn endometrial cancers. CN alterations, mutational data and CN signatures were derived, and associations to clinicopathologic and outcomes data were assessed. Results: In 187 p53abn endometrial cancers, 5 distinct CN signatures were identified. Signature 5 was associated with BRCA1/2 CN loss with features similar to HGSOC HRD signature. Twenty-two percent of potential HRD cases were identified, 35 patients with signature 5, and 8 patients with BRCA1/2 somatic mutations. Signatures 3 and 4 were associated with a high ploidy state, and CCNE1, ERBB2, and MYC amplifications, with mutations in PIK3CA enriched in signature 3. We observed improved overall survival (OS) for patients with signature 2 and worse OS for signatures 1 and 3. Twenty-eight percent of patients had CCNE1 amplification and this subset was enriched with carcinosarcoma histotype. Thirty-four percent of patients, across all histotypes, had ERBB2 amplification and/or HER2 overexpression on IHC, which was associated with worse outcomes. Mutations in PPP2R1A (29%) and FBXW7 (16%) were among the top 5 most common mutations. Conclusions: sWGS and targeted sequencing identified therapeutic opportunities in 75% of patients with p53abn endometrial cancer. Further research is needed to determine the efficacy of treatments targeting these identified pathways within p53abn endometrial cancers.

Cell State of Origin Impacts Development of Distinct Endometriosis-Related Ovarian Carcinoma Histotypes

Abstract Clear cell ovarian carcinoma (CCOC) and endometrioid ovarian carcinoma (ENOC) are ovarian carcinoma histotypes, which are both thought to arise from ectopic endometrial (or endometrial-like) cells through an endometriosis intermediate. How the same cell type of origin gives rise to two morphologically and biologically different histotypes has been perplexing, particularly given that recurrent genetic mutations are common to both and present in nonmalignant precursors. We used RNA transcription analysis to show that the expression profiles of CCOC and ENOC resemble those of normal endometrium at secretory and proliferative phases of the menstrual cycle, respectively. DNA methylation at the promoter of the estrogen receptor (ER) gene (ESR1) was enriched in CCOC, which could potentially lock the cells in the secretory state. Compared with normal secretory-type endometrium, CCOC was further defined by increased expression of cysteine and glutathione synthesis pathway genes and downregulation of the iron antiporter, suggesting iron addiction and highlighting ferroptosis as a potential therapeutic target. Overall, these findings suggest that while CCOC and ENOC arise from the same cell type, these histotypes likely originate from different cell states. This “cell state of origin” model may help to explain the presence of histologic and molecular cancer subtypes arising in other organs. Significance: Two cancer histotypes diverge from a common cell of origin epigenetically locked in different cell states, highlighting the importance of considering cell state to better understand the cell of origin of cancer.

The unique metabolome of clear cell ovarian carcinoma

AbstractClear cell ovarian carcinoma (CCOC) is an aggressive malignancy affecting younger women. Despite ovarian cancer subtypes having diverse molecular and clinical characteristics, the mainstay of treatment for advanced stage disease remains cytotoxic chemotherapy. Late stage CCOC is resistant to conventional chemotherapy, which means a suboptimal outcome for patients affected. Despite detailed genomic, epigenomic, transcriptomic, and proteomic characterisation, subtype‐specific treatment for CCOC has shown little progress. The unique glycogen accumulation defining CCOC suggests altered metabolic pathway activity and dependency. This study presents the first metabolomic landscape of ovarian cancer subtypes, including 42 CCOC, 20 high‐grade serous and 21 endometrioid ovarian carcinomas, together comprising the three most common ovarian carcinoma subtypes. We describe a distinct metabolomic landscape of CCOC compared with other ovarian cancer subtypes, including alterations in energy utilisation and cysteine metabolism. In addition, we identify CCOC‐specific alterations in metabolic pathways including serine biosynthesis and ROS‐associated pathways that could serve as potential therapeutic targets. Our study provides the first in‐depth study into the metabolome of ovarian cancers and a rich resource to support ongoing research efforts to identify subtype‐specific therapeutic targets that could improve the dismal outcome for patients with this devastating malignancy. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Activated immune infiltrates expand opportunities for targeted therapy in p53‐abnormal endometrial carcinoma

AbstractTumor protein p53 mutated/abnormal (p53abn) endometrial carcinomas account for over 50% of deaths but comprise only 15% of all endometrial carcinomas. Most patients show limited response to standard‐of‐care chemotherapy with or without radiotherapy, and only a minority of cases are amenable to targeted therapies like poly‐ADP ribose polymerase (PARP) inhibitors and HER2‐directed therapies. Recent immunotherapy clinical trials have demonstrated remarkable efficacy, not only in mismatch repair deficient (MMRd) tumors but also in a subset of mismatch repair‐proficient (MMRp) tumors. However, the immune microenvironment and its relationship to other therapeutic targets in MMRp endometrial carcinoma remains poorly understood. Here, we characterize the immune microenvironment of p53abn endometrial carcinoma, the most clinically aggressive subtype of MMRp endometrial carcinoma, and correlate antitumor immune signatures with other targetable alterations. We accrued 256 treatment‐naïve p53abn endometrial carcinomas and systemically profiled T‐cell, B‐cell, myeloid, and tumor‐cell populations with multiplex immunofluorescence to assess the tissue localization and functional status of immune cells. Shallow whole‐genome sequencing was performed on a subset of 126 cases. Patterns of immune infiltration were compared to survival outcomes and mutational signatures. Mixture modeling divided p53abn endometrial carcinoma into tumor‐infiltrating lymphocyte (TIL)‐rich and TIL‐poor subsets. Over 50% of tumors were TIL‐rich. TIL‐rich cases overexpressed targetable immune evasion molecules and were associated with longer overall and disease‐specific survival in multivariate analysis. This effect was particularly pronounced in advanced stage disease and in patients who did not receive adjuvant chemotherapy. TIL did not associate with homologous recombination deficient mutational signatures or HER2 amplification. Our findings demonstrate a biological rationale for immunotherapy in a substantial subset of patients with p53abn endometrial cancer and may help inform combination therapies with immune checkpoint inhibition, PARP inhibitors, and anti‐HER2 agents. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Papillary and ductal patterns of mesonephric‐like adenocarcinomas are often overlooked: a retrospective revaluation of over 1000 endometrial carcinomas

AimsMesonephric‐like adenocarcinoma (MLA) of the endometrium is often a diagnostic challenge, due to its morphological resemblance to other more common Müllerian neoplasms. This study aimed to retrospectively identify overlooked MLA in a large endometrial carcinoma cohort, using a combination of immunohistochemistry (IHC), morphology and KRAS sequencing.Methods and resultsIHC was conducted on 1094 endometrial carcinomas, identifying 16 potential MLA cases based on GATA3+ and/or TTF1+ and ER− staining patterns, which subsequently underwent detailed histological review, KRAS sequencing and ProMisE molecular classification. Of the IHC screen‐positive cases, one was positive for both GATA3 and TTF1, nine were positive for GATA3 only and six were positive for TTF1 only. All IHC screen‐positive cases were POLE wild‐type. All five tumours in the NSMP category showed morphological features of MLA, while the three MMRd and eight p53abn tumours did not show MLA morphology. The five cases diagnosed as MLA on review were all originally diagnosed as low‐grade endometrioid adenocarcinoma probably because of rare morphological patterns, being predominantly papillary or ductal. Four of the five cases harboured a KRAS mutation.ConclusionThis study highlights the importance of a comprehensive diagnostic approach for accurately identifying endometrial MLA and for pathologists to be aware of papillary and ductal patterns in endometrial carcinoma assessment. Further exploration into the molecular landscape of MLA is essential for refining diagnostic criteria and developing targeted therapies.

Validation and clinical performance of a single test, DNA based endometrial cancer molecular classifier

We have previously shown that DNA based, single test molecular classification by next generation sequencing (NGS) (Proactive Molecular risk classifier for Endometrial cancer (ProMisE) NGS) is highly concordant with the original ProMisE classifier and maintains prognostic value in endometrial cancer. Our aim was to validate ProMisE NGS in an independent cohort and assess the performance of ProMisE NGS in real world clinical practice to address if there were any practical challenges or learning points for implementation. We evaluated DNA extracted from an external research cohort of 211 endometrial cancer cases diagnosed in 2016 from Germany, Switzerland, and Austria, across seven European centers, comparing standard molecular classification (NGS for A total of 545 endometrial cancers were compared. Prognostic differences in progression free, disease specific, and overall survival between the four molecular subtypes were observed for the NGS classifier, recapitulating the survival curves of original ProMisE. In 28 of 545 (5%) discordant cases (8/211 (4%) in the validation set, 20/334 (6%) in the real world cohort), molecular subtype was able to be definitively assigned in all, based on review of the histopathological features and/or additional immunohistochemistry. DNA based molecular classification identified twice as many 'multiple classifier' endometrial cancers; 37 of 545 (7%) compared with 20 of 545 (4%) with original ProMisE. External validation confirmed that single test, DNA based molecular classification was highly concordant (95%) with original ProMisE classification, with prognostic value maintained, representing an acceptable alternative for clinical practice. Careful consideration of reasons for discordance and knowledge of how to correctly assign multiple classifier endometrial cancers is imperative for implementation.

p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study

AbstractOur objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high‐grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi‐institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36–3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11–2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.

Cystathionine gamma‐lyase‐mediated hypoxia inducible factor 1‐alpha expression drives clear cell ovarian cancer progression

AbstractClear cell ovarian cancer (CCOC) is the second most common ovarian cancer subtype, accounting for 5%–11% of ovarian cancers in North America. Late‐stage CCOC is associated with a worse prognosis compared to other ovarian cancer histotypes, a challenge that has seen limited progress in recent decades. CCOC typically originates within the toxic microenvironment of endometriotic ovarian cysts and is characterized by its intrinsic chemoresistance, a strong hypoxic signature, and abundant expression of cystathionine gamma‐lyase (CTH). CTH is a key enzyme in the transsulfuration pathway and serves as a marker of ciliated cells derived from the Müllerian tract. CTH plays a pivotal role in de novo cysteine synthesis, which is essential for glutathione (GSH) production and redox homeostasis. Using an array of molecular tools and cancer models, including in vivo studies, we demonstrated that CTH expression was induced under various stress conditions, such as exposure to endometriotic cyst content and hypoxia. This induction enables cell survival and creates a differentiation state manifested by CCOC that potentiates tumor progression and metastasis. In addition to regulating redox homeostasis, CTH enhances hypoxia inducible factor 1‐alpha (HIF1α) expression, independently of hydrogen sulfide (H2S) production. Re‐expression of HIF1α in CTH KO cells fully restored metastatic capacity in in vivo models. Co‐expression of CTH and HIF1α proteins was also observed in human CCOC samples. Importantly, targeting CTH in CCOC significantly reduced its metastatic potential in in vivo models and enhanced sensitivity to chemotherapy. These findings underscore that CTH is both a defining feature of CCOC and a promising therapeutic target, not only for CCOC patients but also for those with other CTH‐expressing cancers. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Changes in the tumour microenvironment mark the transition from serous borderline tumour to low‐grade serous carcinoma

AbstractLow‐grade serous ovarian carcinoma (LGSC) is a rare and lethal subtype of ovarian cancer. LGSC is pathologically, biologically, and clinically distinct from the more common high‐grade serous ovarian carcinoma (HGSC). LGSC arises from serous borderline ovarian tumours (SBTs). The mechanism of transformation for SBTs to LGSC remains poorly understood. To better understand the biology of LGSC, we performed whole proteome profiling of formalin‐fixed, paraffin‐embedded tissue blocks of LGSC (n = 11), HGSC (n = 19), and SBTs (n = 26). We identified that the whole proteome is able to distinguish between histotypes of the ovarian epithelial tumours. Proteins associated with the tumour microenvironment were differentially expressed between LGSC and SBTs. Fibroblast activation protein (FAP), a protein expressed in cancer‐associated fibroblasts, is the most differentially abundant protein in LGSC compared with SBT. Multiplex immunohistochemistry (IHC) for immune markers (CD20, CD79a, CD3, CD8, and CD68) was performed to determine the presence of B cells, T cells, and macrophages. The LGSC FAP+ stroma was associated with greater abundance of Tregs and M2 macrophages, features not present in SBTs. Our proteomics cohort reveals that there are changes in the tumour microenvironment in LGSC compared with its putative precursor lesion, SBT. These changes suggest that the tumour microenvironment provides a supportive environment for LGSC tumourigenesis and progression. Thus, targeting the tumour microenvironment of LGSC may be a viable therapeutic strategy. © 2024 The Pathological Society of Great Britain and Ireland.

FOXL2 in adult‐type granulosa cell tumour of the ovary: oncogene or tumour suppressor gene?

AbstractA recurrent mutation in FOXL2 (c.402C>G; p.C134W) is present in over 95% of adult‐type granulosa cell tumours (AGCTs). In contrast, various loss‐of‐function mutations in FOXL2 lead to the development of blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES). BPES is characterised by an eyelid malformation often accompanied with primary ovarian insufficiency. Two recent studies suggest that FOXL2 C402G is a gain‐ or change‐of‐function mutation with altered DNA‐binding specificity. Another study proposes that FOXL2 C402G is selectively targeted for degradation, inducing somatic haploinsufficiency, suggesting its role as a tumour suppressor. The latter study relies on data indicative of an FOXL2 allelic imbalance in AGCTs. Here we present RNA‐seq data as genetic evidence that no real allelic imbalance is observed at the transcriptomic level in AGCTs. Additionally, there is no loss of protein expression in tumours harbouring the mutated allele. These data and other features of this mutation compared to other oncogenes and tumour suppressor genes argue strongly against FOXL2 being a tumour suppressor in this context. Given the likelihood that FOXL2 C402G is oncogenic, targeting the variant protein or its downstream consequences is the most viable path forward to identifying an effective treatment for this cancer. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

STING pathway expression in low‐grade serous carcinoma of the ovary: an unexpected therapeutic opportunity?

AbstractOvarian carcinoma histotypes are distinct diseases with variable clinical outcomes and response to treatment. There is a need for new subtype‐specific treatment modalities, especially for women with widespread and chemo‐resistant disease. Stimulator of interferon genes (STING) is a part of the cGAS–STING pathway that mediates innate immune defence against infectious DNA‐containing pathogens and also detects tumour‐derived DNA and generates intrinsic antitumour immunity. The STING signalling pathway is suppressed by several mechanisms in a variety of malignant diseases and, in some cancers that may be a requirement for cellular transformation. The aim of this study was to use immunohistochemistry to evaluate STING protein expression across normal tissue, paratubal and ovarian cysts, and ovarian tumour histotypes including ovarian carcinomas. Herein, we show that the fallopian tube ciliated cells express STING protein, whereas the secretory cells are negative. STING expression differs among ovarian cancer histotypes; low‐grade serous ovarian carcinomas and serous borderline tumours have uniform high STING expression, while high‐grade serous and endometrioid carcinomas have heterogeneous expression, and clear cell and mucinous carcinomas show low expression. As low‐grade serous carcinomas are known to be genomically stable and typically lack a prominent host immune response, the consistently high STING expression is unexpected. High STING expression may reflect pathway activation or histogenesis and the mechanisms may be different in different ovarian carcinoma histotypes. Further studies are needed to determine whether the STING signalling pathway is active and whether these tumours would be candidates for therapeutic interventions that trigger innate immunity activation.

The proteome of clear cell ovarian carcinoma

AbstractClear cell ovarian carcinoma (CCOC) is the second most common subtype of epithelial ovarian carcinoma. Late‐stage CCOC is not responsive to gold‐standard chemotherapy and results in suboptimal outcomes for patients. In‐depth molecular insight is urgently needed to stratify the disease and drive therapeutic development. We conducted global proteomics for 192 cases of CCOC and compared these with other epithelial ovarian carcinoma subtypes. Our results showed distinct proteomic differences in CCOC compared with other epithelial ovarian cancer subtypes including alterations in lipid and purine metabolism pathways. Furthermore, we report potential clinically significant proteomic subgroups within CCOC, suggesting the biologic plausibility of stratified treatment for this cancer. Taken together, our results provide a comprehensive understanding of the CCOC proteomic landscape to facilitate future understanding and research of this disease. © 2022 The Pathological Society of Great Britain and Ireland.

Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma

Abstract Purpose: The purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC). Experimental Design: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7,436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes, and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 patients with primary HGSC to characterize tumors with concurrent BRCA deficiency and RB1 loss. Results: RB1 loss was associated with longer OS in HGSC but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared with patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA deficiency correlated with transcriptional markers of enhanced IFN response, cell-cycle deregulation, and reduced epithelial–mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. Conclusions: Co-occurrence of RB1 loss and BRCA deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

Loss of SMARCA4 Leads to Intron Retention and Generation of Tumor-Associated Antigens in Small Cell Carcinoma of the Ovary, Hypercalcemic Type

Abstract Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare, deadly form of ovarian cancer that uniformly harbors mutations in SMARCA4, a member of the SWI/SNF chromatin remodeling complex. SWI/SNF impacts RNA splicing, and dysregulation of splicing can generate immunogenic tumor antigens. In this study, we explored the relationship between SMARCA4 loss and RNA splicing dysregulation. SCCOHT primary tumors harbored tumor-associated outlier splicing events compared with normal tissues. Many of the tumor events were retained introns encoding novel peptides predicted to bind to MHC-I complexes. Immune cells were observed in primary SCCOHT tumors, suggesting a potentially immune-reactive tumor microenvironment. Mutations in several switch/sucrose nonfermenting (SWI/SNF) subunits were associated with higher rates of outlier retained introns across tumor types in The Cancer Genome Atlas data. Interestingly, RNA sequencing of isogenic SCCOHT cell lines demonstrated a role for SMARCA4 in intron retention (IR). Distinct protein–protein interactions between splicing factors identified in SCCOHT cell lines supported a role for SMARCA4 in splicing regulation. Furthermore, SWI/SNF localized to genes, which were differentially spliced. Mass spectrometry analyses confirmed expression of some of these novel peptides, and a subset of these are predicted to bind to MHC-I complexes. A pool of these novel peptides derived from retained introns in SCCOHT triggered proliferation and expression of TNFα and INFγ in primary human T cells. Together, these data suggest that SMARCA4 loss in SCCOHT leads to IR. Furthermore, T-cell activation by novel peptides encoded by these tumor-specific splicing events suggests IR could be a source of tumor-associated antigens in SCCOHT. Significance: SCCOHT, a rare ovarian cancer, features splicing dysregulation due to SMARCA4 loss that generates immunostimulatory peptides linked to potential immune responses and therapeutic avenues, challenging traditional views of the role of SMARCA4.

SMARCA4 Loss Increases RNA Polymerase II Pausing and Elevates R-Loops to Inhibit BRCA1-Mediated Repair in Ovarian Cancer

Abstract Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive cancer affecting young women driven by inactivating mutations in SMARCA4, a key SWI/SNF chromatin remodeling gene. To uncover its druggable vulnerabilities, we performed a compound screen and found that SCCOHT cells and tumors were sensitive to PARP inhibitors. Paradoxically, SCCOHT displayed BRCA-deficient traits despite retaining wild-type BRCA1 expression. Elevated R-loop in SCCOHT sequestered BRCA1, limiting its availability for DNA damage repair. Proximity-dependent biotin identification revealed that wild-type SMARCA4, but not its pathogenic variants, promoted RNA polymerase II (Pol II) elongation by mediating the assembly of the polymerase-associated factor 1 complex. Thus, SMARCA4 loss increased Pol II pausing, resulting in elevated R-loops and BRCA1 redistribution. The suppression of BRCA1 activity sensitized SMARCA4-deficient SCCOHT cells and tumors to PARP inhibitors, which was further enhanced by the addition of a CDK9 inhibitor targeting Pol II elongation. Cotargeting PARP/CDK9 also elicited synergistic effects against other undifferentiated ovarian cancer cells with SMARCA4 loss. These findings link SMARCA4 loss to perturbed Pol II elongation and compromised DNA repair by BRCA1, providing a therapeutic opportunity to target SCCOHT and other SWI/SNF-deficient ovarian cancers. Significance: Pol II stalling induced by SMARCA4 loss leads to R-loop accumulation that sequesters BRCA1 to transcription complexes, underlying the sensitivity of SMARCA4-deficient ovarian cancers to inhibitors targeting PARPs and Pol II elongation.